This is a proposal to define the role of blood oxygen affinity as a determinant of oxygen supply to tissue. Specific proposals deal with effect of decreased and increased P50, and other perturbations of oxygen transport, on (1) ability of rats to tolerate hemorrhagic shock; (2) muscle function and muscle oxygen consumption during rest and work in an isolated perfused sciatic nerve-gastrocnemius preparation in rabbits; and (3) cardiac output and distribution measured with microspheres in resting and exercising rats. Another proposal deals with effects in human subjects of congenital alterations of oxygen affinity on submaximal and maximal oxygen consumption and exercise capacity. The final proposal calls for development of a mathematical model describing oxygen delivery and carbon dioxide exchange at the tissue level.